Abstract The objective of this proposal is to better understand the regulation of glucose uptake and storage by the liver in the normal and insulin resistant state. The specific aims are: 1) to determine the importance of hormone and substrate sensing in the brain in control of glucose uptake by the liver, 2) to determine the neural pathways by which portal glucose delivery augments glucose uptake by the liver and decreases glucose uptake by muscle, and 3) to determine the cellular mechanisms by which the portal glucose delivery and insulin trigger liver glucose uptake and the defects that become apparent in insulin resistant state. Studies will be carried out in normal or diet induced insulin resistant conscious dogs. Three weeks before study catheters will be inserted under general anesthesia in the femoral artery, hepatic portal vein and hepatic vein, as well as in other vessels (splenic and jejunal veins, carotid and vertebral arteries, the iliac artery and vein) required by the protocol. The canine model is unique in that it allows the direct measurement of hepatic glucose uptake in vivo. Somatostatin will be infused to disable the endocrine pancreas and glucagon will be replaced intraportally in basal amounts to prevent it from confounding our results. Insulin will be infused at the site and at the rate required by the protocol. Glucose and NEFA will be clamped at the levels required by the study design. The primary variables which we will measure are net hepatic glucose balance, hepatic glucose uptake and production, hepatic glucose oxidation, and net hepatic lactate release as well as glycogen and triglyceride deposition. Muscle glucose metabolism will be assessed in parallel in certain experiments using the hindlimb balance technique. Pharmacologic and surgical tools will be employed as needed to probe targets of interest. Biopsies will be taken from muscle and liver at the end of the experiments so that the physiological changes that we measure can be correlated with the cellular events underpinning them. The proposed studies focus on the regulation of hepatic glucose uptake and glycogen deposition, both of which are dysfunctional in individuals with diabetes. The knowledge gained from these novel experiments have the potential to facilitate the development of new therapeutic approaches to the treatment of post-prandial hyperglycemia in the insulin resistant individual.